Cell surfaces carbohydrates, glycoproteins and glycolipids have multiple biological functions. Abnormalities in glycosylation are one of the basic mechanisms of malfunction (pathology) in living organisms, and particularly in cancers. Consequences of abnormal glycosylation are alteration of cell-cell recognition and signaling, activation of immune response, deregulation of cellular and tissue functions, and if persisting may result in malignant transformation. Malignant transformation and tumor progression can be correlated with specific changes in such complex surface carbohydrates, known as tumor-associated carbohydrate antigens (TACAs).
Glycans are typically the first and potentially the most important interface between cells and their environment. As vital constituents of all living systems, glycans are involved in recognition, adherence, motility and signaling processes. There are several reasons why glycans need to be studied: (1) all cells in living organisms, and viruses, are coated with diverse types of glycans; (2) glycosylation is a form of post- or co-translational modification occurring in all living organisms; and (3) altered glycosylation is an indication of an early and possibly critical point in development of human pathologies. Jun Hirabayashi, Oligosaccharide microarrays for glycomics; 2003, Trends in Biotechnology 21 (4): 141-143; Sen-Itiroh Hakomori, Tumor-associated carbohydrate antigens defining tumor malignancy: Basis for development of and cancer vaccines; in The Molecular Immunology of Complex Carbohydrates-2 (Albert M Wu, ed., Kluwer Academic/Plenum, 2001). These cell-identifying glycosylated molecules include glycoproteins and glycolipids and are specifically recognized by various glycan-recognition proteins. However, the enormous complexity of these interactions, and the lack of well-defined glycan libraries and analytical methods have been major obstacles in the development of glycomics.
The development of nucleotide and protein microarrays has revolutionized genomic, gene expression and proteomic research. The development of glycan microarrays has been slow, however, for a number of reasons. First, it has proven difficult to immobilize a library of chemically and structurally diverse glycans on arrays, beads or the like. Second, glycans are not readily amenable to analysis by many of the currently available molecular techniques (such as rapid sequencing and in vitro synthesis) that are routinely applied to nucleic acids and proteins. However, the use of glycan arrays could expedite screening procedures, making detection of cancer-related glycan epitopes simple and inexpensive.
Important to the successful and effective screening for glycan epitopes is glycan binding to a support that optimally exposes the three-dimensional glycan structure on the array or bead surface. Thus, new glyco-compounds and linking systems are being developed for advancing bioanalytic systems for early cancer detection and target discovery. A glycan array has been described in PCT/US2005/007370 filed Mar. 7, 2005 titled “High Throughput Glycan Microarrays” and U.S. Provisional Patent Application No. 60/629,666 filed Nov. 19, 2004 titled “Development of Blood Based Test Allowing Diagnosis of Neoplasia Status”, both of which are incorporated herein by this reference in their entirety and made a part of this specification. New glyco-compounds and linking systems have been described in U.S. Provisional Patent Application No. 60/833,249 filed Jul. 26, 2006 titled “Bioanalytical Systems, Methods of Use and Business Methods” which is incorporated herein by this reference in its entirety and made a part of this specification.
Detection of diseases, such as cancers, at an early stage is beneficial for effective treatment. Monitoring of cancer and efficacy of cancer therapeutics is also vital to successful treatment and longer-term survival. Protein glycosylation is one of the most common post-translational modifications in mammals and humans. Although post-translational modification, and in particular, various glycans have been associated with the development and progression of cancers, there remains a need for specific and selective glycan markers of disease. The discovery of specific glycan markers, including combinations of markers, which provide for sensitive, selective and precise detection, monitoring, prognosis and/or prediction of cancer will advance the diagnosis and treatment of cancer.